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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900843v1 183/6/3778    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Albaghdadi, H. Articles by Sad, S. PubMed PubMed Citation Articles by Albaghdadi, H. Articles by Sad, S.

Selectively Reduced Intracellular Proliferation of Salmonella enterica Serovar Typhimurium within APCs Limits Antigen Presentation and Development of a Rapid CD8 T Cell Response¹

Homam Albaghdadi^*, Nirmal Robinson^*, Brett Finlay, Lakshmi Krishnan^*, and Subash Sad^2,*,

^* National Research Council Institute for Biological Sciences, Ottawa, Ontario, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada

Ag presentation to CD8⁺ T cells commences immediately after infection, which facilitates their rapid expansion and control of pathogen. This paradigm is not followed during infection with virulent Salmonella enterica serovar Typhimurium (ST), an intracellular bacterium that causes mortality in susceptible C57BL/6J mice within 7 days and a chronic infection in resistant mice (129 x 1SvJ). Infection of mice with OVA-expressing ST results in the development of a CD8⁺ T cell response that is detectable only after the second week of infection despite the early detectable bacterial burden. The mechanism behind the delayed CD8⁺ T cell activation was evaluated, and it was found that dendritic cells/macrophages or mice infected with ST-OVA failed to present Ag to OVA-specific CD8⁺ T cells. Lack of early Ag presentation was not rescued when mice or dendritic cells/macrophages were infected with an attenuated aroA mutant of ST or with mutants having defective Salmonella pathogenicity island I/II genes. Although extracellular ST proliferated extensively, the replication of ST was highly muted once inside macrophages. This muted intracellular proliferation of ST resulted in the generation of poor levels of intracellular Ag and peptide-MHC complex on the surface of dendritic cells. Additional experiments revealed that ST did not actively inhibit Ag presentation, rather it inhibited the uptake of another intracellular pathogen, Listeria monocytogenes, thereby causing inhibition of Ag presentation against L. monocytogenes. Taken together, this study reveals a dichotomy in the proliferation of ST and indicates that selectively reduced intracellular proliferation of virulent pathogens may be an important mechanism of immune evasion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Canadian Institutes of Health Research and the National Research Council.

² Address correspondence and reprint requests to Dr. Subash Sad, National Research Council Institute for Biological Sciences, 1200 Montreal, Road, Ottawa, Ontario, Canada. E-mail address: Subash.sad{at}nrc.ca

³ Abbreviations used in this paper: LM, Listeria monocytogenes; BHI, brain-heart infusion; MOI, multiplicity of infection; NRAMP, natural resistance-associated macrophage protein; SPI, Salmonella pathogenicity island; ST, Salmonella enterica serovar Typhimurium; TRITC, tetramethylrhodamine isothiocyanate; WT, wild type.